: Excess estrogen exposure unopposed by progesterone is associated with increased risk of endometrial cancer. Polymorphisms in genes involved in estrogen metabolism influence the levels of these hormones and may be associated with an altered risk of endometrial cancer. To date no studies of these polymorphisms have been reported in relation to endometrial cancer and little information is available on the relation between these polymorphisms and circulating hormone levels. Endometrial cancer is particularly worth studying because it is the most estrogen responsive tumor and thus modest effects of hormone-metabolizing genes may be more easily detectable. We propose to use the resources of the well-characterized cohort, the Nurses' Health Study, to ascertain the common polymorphisms in key hormone-related genes and to assess whether these genotypes are predictive of future endometrial cancer risk, as well as assessing the functional significance of the variant alleles of these genes by correlating these variants with plasma hormone levels. We will identify and characterize polymorphisms within CYP19 and the progesterone receptor, as well as quantify the association of the known polymorphisms CYP17-A2, COMT-MET, UGT-A(TA)7AA with endometrial cancer and test whether these associations are modified by established endometrial cancer risk factors. These studies will be nested in the subcohort of 32,826 women from Nurses' Health Study who gave blood samples in 1989-1990, and thus will be among the few studies able to prospectively examine these issues in a defined cohort with complete ascertainment of incident cases and comprehensive prospective information on other endometrial cancer risk factors. Matching two controls to each case we will have 98% power to detect a relative risk of 2.0 and 80% power to detect a relative risk of 1.75 for a polymorphism with an 8% homozygous mutant genotype prevalence.